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Non-randomised studies of haemopoietic stem-cell transplantation (HSCT) in systemic sclerosis have shown improvements in lung function and skin flexibility but high treatment-related mortality. We aimed to assess safety and efficacy of autologous non-myeloablative HSCT in a phase 2 trial compared with the standard of care, cyclophosphamide. In our open-label, randomised, controlled phase 2 trial, we consecutively enrolled patients at Northwestern Memorial Hospital (Chicago, IL, USA) who were aged younger than 60 years with diffuse systemic sclerosis, modified Rodnan skin scores (mRSS) of more than 14, and internal organ involvement or restricted skin involvement (mRSS <14) but coexistent pulmonary involvement. We randomly allocated patients 1:1 by use of a computer-generated sequence with a mixed block design (blocks of ten and four) to receive HSCT, 200 mg/kg intravenous cyclophosphamide, and 6·5 mg/kg intravenous rabbit antithymocyte globulin or to receive 1·0 g/m 2 intravenous cyclophosphamide once per month for 6 months. The primary outcome for all enrolled patients was improvement at 12 months' follow-up, defined as a decrease in mRSS (>25% for those with initial mRSS >14) or an increase in forced vital capacity by more than 10%. Patients in the control group with disease progression (>25% increase in mRSS or decrease of >10% in forced vital capacity) despite treatment with cyclophosphamide could switch to HSCT 12 months after enrolment. This study is registered with ClinicalTrials.gov, number NCT00278525. Between Jan 18, 2006, and Nov 10, 2009 we enrolled 19 patients. All ten patients randomly allocated to receive HSCT improved at or before 12 months' follow-up, compared with none of nine allocated to cyclophosphamide (odds ratio 110, 95% CI 14·04–∞; p=0·00001). Eight of nine controls had disease progression (without interval improvement) compared with no patients treated by HSCT (p=0·0001), and seven patients switched to HSCT. Compared with baseline, data for 11 patients with follow-up to 2 years after HSCT suggested that improvements in mRSS (p<0·0001) and forced vital capacity (p<0·03) persisted. Non-myeloablative autologous HSCT improves skin and pulmonary function in patients with systemic sclerosis for up to 2 years and is preferable to the current standard of care, but longer follow-up is needed. None

When it comes to the single life, the women of \"Sex and the City\" know how to keep it real. Karin discusses the success of the show and profiles the show's four actresses--Sarah Jessica Parker, Kim Cattrall, Cynthia Nixon, and Kristin Davis.

En promedio, 9 millones de televidentes sintonizan la serie cada semana para ver las aventuras de la escritora de una columna de sexologia de un periodico, Carrie Bradshaw, y sus amigas, Samantha Jones, propietaria de una compania de relaciones publicas, Charlotte York (Kristin Davis), empleada en una galeria de arte, y Miranda Hobbes (Cynthia Nixon), una abogada. Basado ligeramente en la columna que aparece en el periodico New York Observer \"Sex and the City\" escrita por Candace Bushnell, el programa fue concebido, explica [Darren Star], como \"una comedia sobre el sexo en la que se pudiera decir todo. Esto es territorio no explorado en la television. No obstante me fascinaba que fuesemos una cultura sobresaturada sexualmente y aun asi, al mismo tiempo, es un tabu. Creo que no nos mofamos ni ridiculizmos al sexo lo suficiente\". \"A una amiga de una amiga le sucedio eso realmente\", explica King. \"Y a su vez su amiga tuvo que pedirle a otra amiga que le ayudara a sacarlo. Me dije a mi mismo: 'Eso si que es amistad'\".

Allochronic speciation, where reproductive isolation between populations of a species is facilitated by a difference in reproductive timing, depends on abiotic factors such as seasonality and biotic factors such as diapause intensity. These factors are strongly influenced by latitudinal trends in climate, so we hypothesized that there is a relationship between latitude and divergence among populations separated by life history timing. Hyphantria cunea (the fall webworm), a lepidopteran defoliator with red and black colour morphs, is hypothesized to be experiencing an incipient allochronic speciation. However, given their broad geographic range, the strength of allochronic speciation may vary across latitude. We annotated >11,000 crowd-sourced observations of fall webworm to model geographic distribution, phenology, and differences in colour phenotype between morphs across North America. We found that red and black morph life history timing differs across North America, and the phenology of morphs diverges more in warmer climates at lower latitudes. We also found some evidence that the colour phenotype of morphs also diverges at lower latitudes, suggesting reduced gene flow between colour morphs. Our results demonstrate that seasonality in lower latitudes may increase the strength of allochronic speciation in insects, and that the strength of sympatric speciation can vary along a latitudinal gradient. This has implications for our understanding of broad-scale speciation events and trends in global biodiversity.

Surgical antimicrobial prophylaxis (SAP) is a leading indication for antibiotic use in the hospital setting, with demonstrated high rates of inappropriateness. Decision-making for SAP is complex and multifactorial. A greater understanding of these factors is needed to inform the design of targeted antimicrobial stewardship interventions and strategies to support the optimization of SAP and its impacts on patient care. A qualitative case study exploring the phenomenon of SAP decision-making. Focus groups were conducted with surgeons, anaesthetists, theatre nurses and pharmacists across one private and two public hospitals in Australia. Thematic analysis was guided by the Theoretical Domains Framework (TDF) and the Capabilities, Opportunities, Motivators-Behaviour (COM-B) model. Fourteen focus groups and one paired interview were completed. Ten of the fourteen TDF domains were identified as relevant. Thematic analysis revealed six significant themes mapped to the COM-B model, and subthemes mapped to the relevant TDF domains in a combined framework. Key themes identified were: 1) Low priority for surgical antimicrobial prophylaxis prescribing skills; 2) Prescriber autonomy takes precedence over guideline compliance; 3) Social codes of prescribing reinforce established practices; 4) Need for improved communication, documentation and collection of data for action; 5) Fears and perceptions of risk hinder appropriate SAP prescribing; and 6) Lack of clarity regarding roles and accountability. SAP prescribing is a complex process that involves multiple professions across the pre-, intra- and post-operative surgical settings. The utilisation of behaviour change frameworks to identify barriers and enablers to optimal SAP prescribing supports future development of theory-informed antimicrobial stewardship interventions. Interventions should aim to increase surgeon engagement, enhance the prioritisation of and accountability for SAP, and address the underlying social factors involved in SAP decision-making, such as professional hierarchy and varied perceptions or risks and fears.

Shared decision-making (SDM) is a process in which healthcare providers (HCPs) and patients make health-related decisions collaboratively, guided by the best available evidence. Previous research suggests that emerging adults (aged 18-29) with mental health concerns might prefer SDM over traditional approaches; however, it remains unclear whether prevalent symptoms of anxiety, depression, or health-related quality of life (HRQL) are associated with the level of SDM that occurs during a clinical encounter. This study explored whether prevalent symptoms of anxiety, depression or HRQL among emerging adults were associated with the perceived level of SDM involvement during a single clinic visit at a primary care or community addiction and mental health (AMH) setting. A cross-sectional survey was conducted using a subset of data (emerging adults and their HCPs) obtained from an overarching study on SDM in adults (18-64 years) in Alberta, Canada. Sociodemographic data were collected and reported descriptively. SDM was the primary outcome variable and was measured dyadically (i.e., the mean score between HCPs and patients) using the Alberta Shared Decision-Making Instrument (ASK-MI). Symptoms of patient anxiety/depression and HRQL were measured using the Hospital Anxiety and Depression Scale (HADS) and the EQ-5D-5L. Pearson R correlation matrices were conducted to explore relationships between SDM, anxiety/depression, HRQL, and demographic variables. Forty-two emerging adult patients and 31 HCP dyads were recruited from six community AMH settings and eight primary care settings. The mean SDM dyad rating was 8.69 (SD, ± 2.01), indicating an \"excellent\" level of SDM. Symptoms of anxiety, depression, and HRQL were not significantly correlated with SDM dyad ratings during the clinic visit. Post hoc analyses showed that patient age was inversely related to SDM dyad ratings; R = -0.34, p = 0.03. In this study, emerging adults reported high levels of perceived engagement in SDM, regardless of their HRQL or symptoms of anxiety and depression. However, several limitations, such as the risk of performance bias, should be considered when interpreting these findings. To strengthen the evidence base, future research should aim to address these limitations.

Parkinson’s disease is characterized by accumulation of α-synuclein (αSyn). Release of oligomeric/fibrillar αSyn from damaged neurons may potentiate neuronal death in part via microglial activation. Heretofore, it remained unknown if oligomeric/fibrillar αSyn could activate the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome in human microglia and whether anti-αSyn antibodies could prevent this effect. Here, we show that αSyn activates the NLRP3 inflammasome in human induced pluripotent stem cell (hiPSC)-derived microglia (hiMG) via dual stimulation involving Toll-like receptor 2 (TLR2) engagement and mitochondrial damage. In vitro, hiMG can be activated by mutant (A53T) αSyn secreted from hiPSC-derived A9-dopaminergic neurons. Surprisingly, αSyn–antibody complexes enhanced rather than suppressed inflammasome-mediated interleukin-1β (IL-1β) secretion, indicating these complexes are neuroinflammatory in a human context. A further increase in inflammation was observed with addition of oligomerized amyloid-β peptide (Aβ) and its cognate antibody. In vivo, engraftment of hiMG with αSyn in humanized mouse brain resulted in caspase-1 activation and neurotoxicity, which was exacerbated by αSyn antibody. These findings may have important implications for antibody therapies aimed at depleting misfolded/aggregated proteins from the human brain, as they may paradoxically trigger inflammation in human microglia.

Background In people with chronic obstructive pulmonary disease (COPD) on inhaled corticosteroid/long-acting β 2 -agonist (ICS/LABA) therapy, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommends stepping up to ICS/long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) in those with exacerbations or switching to LAMA/LABA in those with major symptoms. However, the effect of stepping up to ICS/LAMA/LABA versus switching to LAMA/LABA on exacerbation risk is unclear. This analysis evaluated the effect of escalating to ICS/LAMA/LABA versus switching to LAMA/LABA or staying on ICS/LABA on lung function and exacerbation rates in symptomatic individuals with COPD without a recent exacerbation history from KRONOS. Methods In KRONOS (NCT02497001), symptomatic participants with moderate-to-very severe COPD (exacerbations in the prior year were not required for inclusion) were randomized to budesonide/glycopyrronium/formoterol fumarate dihydrate 320/14.4/10 μg (BGF), glycopyrronium/formoterol fumarate dihydrate 14.4/10 μg (GFF), budesonide/formoterol fumarate dihydrate 320/10 μg (BFF) via metered-dose inhaler, or budesonide/formoterol fumarate dihydrate 400/12 μg via dry-powder inhaler (BUD/FORM) for 24 weeks. In participants without a recent exacerbation history on ICS/LABA in the 30 days before screening, morning pre-dose trough FEV 1 change from baseline and moderate/severe exacerbation rates over 24 weeks were analyzed post-hoc using linear repeated measures models and negative binomial regression, respectively, and participants escalated to ICS/LAMA/LABA (BGF) were compared with those switching to LAMA/LABA (GFF) or staying on ICS/LABA (BFF or BUD/FORM). Results On stepping up to BGF, least square means (95% confidence interval [CI]) differences for morning pre-dose trough FEV 1 change from baseline over 24 weeks was similar versus switching to GFF (12 [–21, 44] mL) but greater versus staying on ICS/LABA (BGF vs. BFF, 106 [64, 148] mL; BGF vs. BUD/FORM, 55 [12, 97] mL). Moderate/severe exacerbations were experienced by participants in all treatment arms (BGF, 14.9%; GFF, 24.0%; BFF 17.6%; BUD/FORM, 21.2%). Exacerbation risk was reduced when stepping up to BGF versus switching to GFF (rate ratio [95% CI]: 0.57 [0.35, 0.94]); rate ratios (95% CI) for BGF versus remaining on ICS/LABA were 0.93 (0.47, 1.82) with BFF and 0.62 (0.33, 1.18) with BUD/FORM. Conclusions People with symptomatic COPD and no recent exacerbation history previously on ICS/LABA had reduced exacerbation risk after escalating to ICS/LAMA/LABA versus switching to LAMA/LABA, and improved lung function versus staying on ICS/LABA. Trial registration ClinicalTrials.gov registry number NCT02497001 (registration date, 7 July 2015).

Background Japanese guidelines recommend triple inhaled corticosteroid (ICS)/long-acting muscarinic antagonist (LAMA)/long-acting β 2 -agonist (LABA) therapy in patients with chronic obstructive pulmonary disease (COPD) and no concurrent asthma diagnosis who experience frequent exacerbations and have blood eosinophil (EOS) count ≥ 300 cells/mm 3 , and in patients with COPD and asthma with continuing/worsening symptoms despite receiving dual ICS/LABA therapy. These post-hoc analyses of the KRONOS study in patients with COPD and without an asthma diagnosis, examine the effects of fixed-dose triple therapy with budesonide/glycopyrronium/formoterol fumarate dihydrate (BGF) versus dual therapies on lung function and exacerbations based on blood EOS count – focusing on blood EOS count 100 to < 300 cells/mm 3 – as a function of exacerbation history and COPD severity. Methods In KRONOS, patients were randomized to receive treatments that included BGF 320/14.4/10 µg, glycopyrronium/formoterol fumarate dihydrate (GFF) 14.4/10 µg, or budesonide/formoterol fumarate dihydrate (BFF) 320/10 µg via metered dose inhaler (two inhalations twice-daily for 24 weeks). These post-hoc analyses assessed changes from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV 1 ) over 12–24 weeks and moderate or severe COPD exacerbations rates over 24 weeks. The KRONOS study was not prospectively powered for these subgroup analyses. Results Among patients with blood EOS count 100 to < 300 cells/mm 3 , least squares mean treatment differences for lung function improvement favored BGF over BFF in patients without an exacerbation history in the past year and in patients with moderate and severe COPD, with observed differences ranging from 62 ml to 73 ml across populations. In this same blood EOS population, moderate or severe exacerbation rates were reduced for BGF relative to GFF by 56% in patients without an exacerbation history in the past year, by 47% in patients with moderate COPD, and by 50% in patients with severe COPD. Conclusions These post-hoc analyses of patients with moderate-to-very severe COPD from the KRONOS study seem to indicate clinicians may want to consider a step-up to triple therapy in patients with persistent/worsening symptoms with blood EOS count > 100 cells/mm 3 , even if disease severity is moderate and there is no recent history of exacerbations. Trial registration ClinicalTrials.gov registry number NCT02497001 (registration date, 13 July 2015).

More smokers report using e-cigarettes to help them quit than FDA-approved pharmacotherapy. To assess the association of e-cigarettes with future abstinence from cigarette and tobacco use. Cohort study of US sample, with annual follow-up. US adult (ages 18+) daily cigarette smokers identified at Wave 1 (W1; 2013-14) of the PATH Study, who reported a quit attempt before W2 and completed W3 (n = 2443). Use of e-cigarettes, pharmacotherapy (including nicotine replacement therapy), or no product for last quit attempt (LQA), and current daily e-cigarette use at W2. Propensity score matching (PSM) of groups using different methods to quit. 12+ months abstinence at W3 from cigarettes and from all tobacco (including e-cigarettes). 30+ days abstinence at W3 was a secondary outcome. Among daily smokers with an LQA, 23.5% used e-cigarettes, 19.3% used pharmacotherapy only (including NRT) and 57.2% used no product. Cigarette abstinence for 12+ months at W3 was ~10% in each group. Half of the cigarette abstainers in the e-cigarette group were using e-cigarettes at W3. Different methods to help quitting had statistically comparable 12+ month cigarette abstinence at W3 (e-cigarettes vs no product: Risk Difference (RD) = 0.01, 95% CI: -0.04 to 0.06; e-cigarettes vs pharmacotherapy: RD = 0.02, 95% CI:-0.04 to 0.09). Likewise, daily e-cigarette users at W2 did not show a cessation benefit over comparable no-e-cigarette users and this finding was robust to sensitivity analyses. Abstinence for 30+ days at W3 was also similar across products. The frequency of e-cigarette use during the LQA was not assessed, nor was it possible to assess continuous abstinence from the LQA. Among US daily smokers who quit cigarettes in 2014-15, use of e-cigarettes in that attempt compared to approved cessation aids or no products showed similar abstinence rates 1-2 years later.